Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Despite recent declines in coronary heart disease ("CHD") mortality, CHD is still responsible for more than 500,000 deaths in the U.S. annually. It is estimated that CHD, directly or indirectly, causes the U.S. more than $100 billion a year. Risk factors for atherosclerotic coronary heart disease include, among several factors, hypertension, diabetes mellitus, family history, male gender, cigarette smoking and high serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is generally associated with a significant elevation of risk. Cholesteryl esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Lowering of plasma cholesterol in patients with hypercholesterolemia has been of intense focus in pharmaceutical research in recent years.
Typically, cholesterol is carried in the blood of warm-blooded animals in certain lipid-protein complexes such as, for example, chylomicrons, very low density lipoprotein ("VLDL"), low density lipoprotein ("LDL"), and high density lipoprotein ("HDL"). It is widely accepted that LDL functions in a way that directly results in deposition of the LDL cholesterol in the blood-vessel wall and that HDL functions in a way that results in the HDL picking up cholesterol from the vessel wall and transporting it to the liver where it is metabolized [M. S. Brown and J. L. Goldstein, Ann. Rev. Biochem., 52 (1983), 223; G. L. Miller, Ann. Rev. Med., 31 (1980), 97]. For example, in various epidemiological studies, the LDL cholesterol levels correlate well with the risk of coronary heart disease whereas the HDL cholesterol levels are inversely associated with coronary heart disease [J. G. Patton et al, Clin. Chem., 29 (1983), 1890]. It is generally accepted by those skilled in the art that reduction of abnormally high LDL cholesterol levels is effective therapy not only in the treatment of hypercholesterolemia but also in the treatment of atherosclerosis. Accordingly, it is desirable to provide a method for reducing LDL cholesterol in patients with hypercholesterolemia.
Several products are commercially available from drug manufacturers for the lowering of cholesterol. Some illustrative types and commercial products are: resins (for example, QUESTRAN.RTM. which is cholestyramine ion exchange resin from Bristol-Myers Squibb Corporation, Princeton, N.J.; and COLESTID.RTM. which is the hydrochloride of the polymer of N-(2-aminoethyl)-N'-[2-[(2-aminoethyl)amino]ethyl]-1,2-ethanediamine with (chloromethyl)oxirane) available from Pharmacia-Upjohn Company, Peapack, N.J.); fibrates (for example, LOPID.RTM. which is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid available from Warner-Lambert Company, Morris Plains, N.J.; and TRICOR.RTM. which is a fenofibrate available from Abbott Laboratories, Chicago, Ill.); and statins (for example, lovastatin as MEVACOR.RTM. available from Merck & Company, Whitehouse Station, N.J.; fluvastatin as LESCOL.RTM. from Novartis Corporation, East Hanover, N.J.; simvastatin as ZOCOR.RTM. from Merck & Company; pravastatin as PRAVACHOL.RTM. from Bristol Myers Squibb Corporation; atorvastatin as LIPITOR.RTM. from Warner-Lambert Company; and cerivastatin as BAYCOL.RTM. from Bayer Corporation, West Haven, Conn.).
U.S. Pat. Nos. 5,767,115; 5,744,467; 5,698,548; 5,688,787; 5,656,624; 5,633,246; 5,631,365; and 5,624,920 (all assigned to Schering Corporation, Kenilworth, N.J.) disclose various azetidinones and substituted p-lactam compounds as cholesterol lowering agents.
There is a continuing interest in finding novel cholesterol lowering agents.
It is an objective of this invention to find useful cholesterol lowering agents.
It is a farther objective of this invention to find methods of lowering cholesterol and treating diseases associated with high cholesterol, using novel compounds.
Other objectives and advantages of the present invention will be apparent to those skilled in the art from the accompanying description and claims.